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Graziano F, Catalano G, Cascinu S. Chemotherapy for Advanced Pancreatic Cancer: The History is Changing. TUMORI JOURNAL 2018; 84:308-11. [PMID: 9678612 DOI: 10.1177/030089169808400304] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Until recently, chemotherapy was considered ineffective in pancreatic cancer and these patients received best supportive care only. Now, there is evidence that chemotherapy may influence the natural history of the disease by prolonging survival and there are data on its role as an effective tool for the improvement of physical conditions in patients with advanced disease. The results are far from conclusive, and only partially satisfying but they represent a step forward.
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Affiliation(s)
- F Graziano
- Sezione di Oncologia Sperimentale, Azienda Ospedaliera Ospedale S. Salvatore, Pesaro, Italy
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Lee SW, Lee HL, Han NI, Kwon JH, Nam SW, Jang JW, Bae SH, Choi JY, Yoon SK. Transarterial infusion of epirubicin and cisplatin combined with systemic infusion of 5-fluorouracil versus transarterial chemoembolization using doxorubicin for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a retrospective analysis. Ther Adv Med Oncol 2017; 9:615-626. [PMID: 28974984 PMCID: PMC5613859 DOI: 10.1177/1758834017728018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 07/03/2017] [Indexed: 01/18/2023] Open
Abstract
Background: More than one-third of hepatocellular carcinoma (HCC) patients are diagnosed at advanced stage with portal vein tumor thrombosis (PVTT) or extrahepatic metastasis. However, the outcomes of current therapeutic approaches are unsatisfactory. As a novel therapeutic strategy for unresectable HCC with PVTT, we analyzed the outcomes of transarterial infusion of epirubicin and cisplatin combined with systemic infusion of 5-fluorouracil (TAC-ECF) and compared its therapeutic effects and toxicity with transarterial chemoembolization (TACE) using doxorubicin (DOX). Methods: A total of 540 consecutive HCC patients who received TACE at the Catholic Medical Center between January 2007 and November 2013 were enrolled. Of these patients, we retrospectively analyzed 129 Barcelona clinic liver cancer stage C HCC patients with PVTT who received either TAC-ECF or TACE using DOX. Results: The objective tumor response rate was higher in the TAC-ECF group, with 31.3% objective response rate after TAC-ECF compared to 10% after DOX treatment (p = 0.004). Median follow-up period was 7 months (range, 1–57 months). The overall survival rate was also significantly higher in the TAC-ECF group compared to the DOX group (median 9.3 versus 4.6 months, p < 0.0001). Multivariate analysis revealed that TAC-ECF and extrahepatic metastasis were independent predictive factors for overall survival (p < 0.0001 and p = 0.002 respectively). No serious adverse effects developed in both groups. Conclusions: TAC-ECF therapy was tolerable and showed higher overall survival rate and tumor response compared to the conventional TACE DOX in advanced stage HCC patients with PVTT. Therefore, TAC-ECF may be considered as an effective treatment option for patients with unresectable HCC.
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Affiliation(s)
- Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hae Lim Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Nam Ik Han
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soon Woo Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 137-701, Republic of Korea
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Li J, Podoltsev N, Saif MW. Management of advanced pancreatic cancer. Expert Rev Clin Pharmacol 2014; 2:527-41. [DOI: 10.1586/ecp.09.30] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Abstract
OBJECTIVES In Belgium, combination chemotherapy of cisplatin and 5-fluorouracil + leucovorin (CFL) according to the modified de Gramont schedule is the treatment of choice in second line for metastatic pancreatic cancer. We retrospectively analyzed survival data in 2 Belgian centers in a nonselected population. METHODS Between January 2004 and October 2011, 48 patients with histologically proven recurrent or unresectable pancreatic adenocarcinoma who had received CFL as second-line treatment were identified. We retrospectively analyzed the following parameters: progression-free survival (PFS1 and PFS2) for each line (after the start of first and second line), overall survival (OS), and growth modulation index. RESULTS The median PFS1 was 5.4 months (95% confidence interval [CI], 4.1-6.6). The median PFS2 was 3.6 months (95% CI, 2-5.2). The median OS was 12 months (95% CI, 9.3-14.7). Twenty-three percent of patients had a growth modulation index >1.33. CONCLUSION We show an OS of 12 months with gemcitabine in first-line and CFL in second-line therapy for pancreatic cancer. Sequential therapy with good OS and good quality of life may be preferred to strong upfront therapy in an incurable disease such as pancreatic cancer.
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Sun W, Metz JM, Gallagher M, O’Dwyer PJ, Giantonio B, Whittington R, Haller DG. Two phase I studies of concurrent radiation therapy with continuous-infusion 5-fluorouracil plus epirubicin, and either cisplatin or irinotecan for locally advanced upper gastrointestinal adenocarcinomas. Cancer Chemother Pharmacol 2010; 67:621-7. [DOI: 10.1007/s00280-010-1365-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2009] [Accepted: 05/06/2010] [Indexed: 11/29/2022]
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Solimando DA, Waddell JA. Epirubicin, Cisplatin, and Fluorouracil (ECF) Regimen. Hosp Pharm 2009. [DOI: 10.1310/hpj4412-1072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparing, dispensing, and administering antineoplastic therapy and to the agents, commercially available and investigational, used to treat malignant diseases.
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The flavonoid apigenin potentiates the growth inhibitory effects of gemcitabine and abrogates gemcitabine resistance in human pancreatic cancer cells. Pancreas 2009; 38:409-15. [PMID: 19142175 DOI: 10.1097/mpa.0b013e318193a074] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES The aim of the study was to evaluate the effect of combination therapy of apigenin and gemcitabine on cell proliferation, the cell cycle, and gemcitabine resistance in human pancreatic cancer cells. METHODS Cell counting was used to assess the effect of single-agent and combination treatment on the proliferation of CD18 and AsPC-1 pancreatic cancer cells. Flow cytometry was performed to assess the effect of combination treatment on cell cycle progression and induction of apoptosis. Western blot analysis was used to evaluate phosporylated AKT (pAkt) and cell cycle proteins. The effect of apigenin on gemcitabine-resistant AsPC-1 cells was assessed via thymidine incorporation. RESULTS Apigenin in combination with gemcitabine inhibited pancreatic cancer cell proliferation more than either agent alone. Combination treatment induced both S and G2/M phase arrest and increased apoptosis. Apigenin down-regulated pAkt expression and abrogated gemcitabine-mediated pAkt induction. In gemcitabine-resistant AsPC-1 cells, apigenin significantly inhibited cell proliferation in a dose-dependent manner. CONCLUSION Combination treatment with apigenin and gemcitabine inhibited pancreatic cancer cell growth via cell cycle arrest, down-regulation of the prosurvival factor pAkt, and induction of apoptosis. Combination therapy may prove useful for the treatment of pancreatic cancer.
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Schønnemann KR, Jensen HA, Yilmaz M, Jensen BY, Larsen O, Pfeiffer P. Phase II study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first-line therapy in patients with non-resectable gastric cancer. Br J Cancer 2009; 99:858-61. [PMID: 19238627 PMCID: PMC2538753 DOI: 10.1038/sj.bjc.6604569] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Epirubicin, cisplatin and continuous infusion of 5-FU is a widely used palliative regimen in patients with gastric cancer. If cisplatin is substituted by oxaliplatin and 5-FU by capecitabine this regimen can be administered in the outpatient setting. Dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy and it is recommended to give oxaliplatin as a 120 min infusion. However, in patients with colorectal cancer a 30 min infusion of oxaliplatin can safely be administered without increasing neurotoxicity, standard infusion time is 30 min at our departments. In our phase I study the recommended doses of EXE was established (Dupont et al, 2006). Patients with non-resectable gastric adenocarcinoma were eligible. Patients received EXE (epirubicin 50 mg m(-2) day 1; capecitabine 1000 mg m(-2) day(-1) continuously and oxaliplatin 130 mg m(-2) day 1) as outpatient therapy every third week for a maximum of 8 cycles. From June 2004 to September 2005, we enroled 54 patients. Median age was 60 years (31-74 years) Median number of courses was 6 (1-8). Response rate was 45%. Median PFS was 6.8 (5.2-7.9) months and median survival was 10.1 (7.9-1.1) months. Most important grade 3 toxicities were as follows: nausea, vomiting, and diarrhoea (6%). Neurotoxicity grade 2 was seen in 36.5%. We therefore conclude, that EXE every third week is a convenient regimen that easily can be administrated in the outpatient setting but the regimen needs further evaluation in a phase III study.
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Affiliation(s)
- K R Schønnemann
- Department of Oncology, Odense University Hospital, Odense C 5000, Denmark.
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Sofuni A, Itoi T, Itokawa F, Tsuchiya T, Kurihara T, Ishii K, Tsuji S, Ikeuchi N, Moriyasu F. Usefulness of contrast-enhanced ultrasonography in determining treatment efficacy and outcome after pancreatic cancer chemotherapy. World J Gastroenterol 2008; 14:7183-91. [PMID: 19084932 PMCID: PMC2776876 DOI: 10.3748/wjg.14.7183] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate if contrast-enhanced ultrasono-graphy (CE-US) is useful for determining treatment efficacy and outcome in the early stages of pancreatic cancer chemotherapy by assessing changes in intratumor hemodynamics using CE-US with a contrast agent.
METHODS: The subjects were 34 patients with unresectable advanced pancreatic cancer treated by chemotherapy. CE-US was assessed after every treatment (course) completion under the same conditions, and patients were divided into two groups according to the intratumor enhancement pattern: Vascular rich (R) group and vascular poor (P) group.
RESULTS: After the second course of treatment, R group in intratumor hemodynamics had 18 patients, and P group had 16 patients. The reduction rates of serum CA19-9 level after chemotherapy which decreased to half or less of the baseline level were 2/15 (0.1%) in P group, but 11/16 (69%) in R group (P = 0.006). When the mean number of courses of chemotherapy and outcome were compared, P group had a mean number of courses of 4.9 (R group, 10.2) and mean survival time (MST) of 246 d (R group, 402 d), showing that outcome was significantly better in R group (P = 0.006).
CONCLUSION: CE-US revealed that the change in intratumor blood flow correlated with both serum CA19-9 level and outcome. Patients with serum CA19-9 that decreased to less than half the baseline level, and patients with an abundant intratumor blood flow, had a significantly better outcome. Thus, CE-US is potentially useful for evaluating treatment efficacy and outcome in the early stages of pancreatic cancer chemotherapy.
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Dupont J, Jensen HA, Jensen BV, Pfeiffer P. Phase I study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first line therapy in patients with non-resectable gastric cancer. Acta Oncol 2007; 46:330-5. [PMID: 17450468 DOI: 10.1080/02841860600949578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
A phase I trial of short-time oxaliplatin (E), capecitabine (X) and epirubicin (E) for patients with metastatic gastric cancer was initiated to establish the recommended dose for further therapy with short-time EXE. Patients received out-patient therapy with a fixed dose of epirubicin 50 mg/m2 day 1; escalating doses of capecitabine (1,000 to 1,250 mg/m2/day continuously) and escalating doses of oxaliplatin (85 to 130 mg/m2 day 1 as a 30 minutes infusion). Cycles were repeated every 21 days for a maximum of 8 cycles. From June 2003 to June 2004, 31 patients were treated. Median age was 61 years (39-75 years), and median performance status was 0 (0-2). At level 3, one of six patients developed DLT and at dose level 4, two of six patients developed DLT (both patients had grade 4 hematological toxicities) and thus further dose escalation was not attempted. Median number of cycles was 6 (1-8), median survival was 9.2 months and median TTP was 7.5 months. A combination of epirubicin 50 mg/m2 day 1, capecitabine 1,000 mg/m2 continuously and oxaliplatin 130 mg/m2 day 1 each 3 weeks is an easily administered and well tolerated out-patient regimen for patients with non-resectable gastric cancer.
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Affiliation(s)
- Jeanette Dupont
- Department of Oncology, Odense University Hospital, Odense, Denmark.
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Abstract
Unresectable pancreatic cancers have an extremely dismal prognosis and chemoresistant nature. The treatment of pancreatic cancer is still problematic. Gemcitabine is a promising new agent that has been studied recently for palliation of advanced pancreatic cancer. However, the response rates have been highly variable, and are often irreproducible. To improve this low response rate, various treatments are needed because no standard treatment exists. Intra-arterial chemotherapy is considered to take advantage of the first pass effect of the drug, generating higher local drug concentrations in tumor cells with lower toxicity. Regional intra-arterial chemotherapy may provide high levels of cytostatic concentrations within the tumor and, simultaneously, a low rate of systemic side effects compared with systemic administration of anti-neoplastic drugs. Intra-arterial chemotherapy has been introduced as an alternative treatment for advanced pancreatic cancer. Further clinical trials of this method should be subjected to a prospective randomized controlled study for advanced pancreatic cancer.
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Affiliation(s)
- Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Second Hospital, Teraji 280-7, Niigata 950-1104, Japan.
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Ikeda O, Tamura Y, Nakasone Y, Shiraishi S, Kawanaka K, Tomiguchi S, Yamashita Y, Takamori H, Kanemitsu K, Baba H. Comparison of intrahepatic and pancreatic perfusion on fusion images using a combined SPECT/CT system and assessment of efficacy of combined continuous arterial infusion and systemic chemotherapy in advanced pancreatic carcinoma. Cardiovasc Intervent Radiol 2007; 30:912-21. [PMID: 17710478 DOI: 10.1007/s00270-007-9134-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2006] [Revised: 05/04/2007] [Accepted: 05/14/2007] [Indexed: 01/27/2023]
Abstract
PURPOSE The purpose of this study was to compare intrahepatic and pancreatic perfusion on fusion images using a combined single-photon emission computed tomography (SPECT)/CT system and to evaluate the efficacy of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in the treatment of advanced pancreatic carcinoma. MATERIALS AND METHODS CTAI was performed in 33 patients (22 men, 11 women; age range, 35-77 years; mean age, 60 years) with stage IV pancreatic cancer with liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. In all patients we obtained fusion images using a combined SPECT/CT system. Pancreatic perfusion on fusion images was classified as perfusion presence or as perfusion absent in the pancreatic cancer. Using WHO criteria we recorded the tumor response after 3 months on multislice helical CT scans. Treatment effects were evaluated based on the pancreatic cancer, liver metastasis, and factors such as intrahepatic and pancreatic perfusion on fusion images. For statistical analysis we used the chi-square test; survival was evaluated by the Kaplan Meier method (log-rank test). RESULTS On fusion images, pancreatic and intrahepatic perfusion was recorded as hot spot and as homogeneous distribution, respectively, in 18 patients (55%) and as cold spot and heterogeneous distribution, respectively, in 15 (45%). Patients with hot spot in the pancreatic tumor and homogeneous distribution in the liver manifested better treatment results (p < 0.05 and p < 0.01, respectively). Patients with hot spot both in the pancreatic cancer and in the liver survived longer than those with cold spot in the pancreatic cancer and heterogeneous distribution in the liver (median +/- SD, 16.0 +/- 3.7 vs. 8.0 +/- 1.4 months; p < 0.05). CONCLUSIONS We conclude that in patients with advanced pancreatic cancer, CTAI with systemic chemotherapy appeared to be effective and may prolong their survival. The development of a reservoir port system allowing for the homogeneous distribution of anticancer drugs is necessary to improve the prognosis of patients with advanced pancreatic cancer.
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MESH Headings
- Adenocarcinoma/blood supply
- Adenocarcinoma/diagnostic imaging
- Adenocarcinoma/mortality
- Adenocarcinoma/secondary
- Adenocarcinoma/therapy
- Adult
- Aged
- Antimetabolites, Antineoplastic/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Carcinoma, Pancreatic Ductal/blood supply
- Carcinoma, Pancreatic Ductal/diagnostic imaging
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/therapy
- Catheters, Indwelling
- Chemoembolization, Therapeutic/methods
- Deoxycytidine/administration & dosage
- Deoxycytidine/analogs & derivatives
- Equipment Design
- Female
- Fluorouracil/administration & dosage
- Humans
- Infusions, Intra-Arterial
- Injections, Intravenous
- Kaplan-Meier Estimate
- Liver Circulation
- Liver Neoplasms/blood supply
- Liver Neoplasms/diagnostic imaging
- Liver Neoplasms/mortality
- Liver Neoplasms/secondary
- Liver Neoplasms/therapy
- Male
- Middle Aged
- Neoplasm Staging
- Pancreatic Neoplasms/blood supply
- Pancreatic Neoplasms/diagnostic imaging
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/therapy
- Prospective Studies
- Regional Blood Flow
- Time Factors
- Tomography, Emission-Computed, Single-Photon/methods
- Tomography, Spiral Computed/methods
- Treatment Outcome
- Gemcitabine
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Affiliation(s)
- Osama Ikeda
- Department of Diagnostic Radiology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, 1-1-1, Honjo Kumamoto 860-8556, Japan.
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Reni M, Cereda S, Bonetto E, Viganò MG, Passoni P, Zerbi A, Balzano G, Nicoletti R, Staudacher C, Di Carlo V. Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2006; 59:361-7. [PMID: 16807732 DOI: 10.1007/s00280-006-0277-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2006] [Accepted: 05/31/2006] [Indexed: 01/09/2023]
Abstract
BACKGROUND PEFG regimen (cisplatin and epirubicin 40 mg/m2 day 1, gemcitabine 600 mg/m2 days 1 and 8, 5-fluorouracil (FU) 200 mg/m2/day continuous infusion) significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine in a previous phase III trial. This regimen was subsequently modified in a dose-finding study by increasing dose intensity of cisplatin and epirubicin (both at 30 mg/m2 every 14 days) and of gemcitabine (at 800 mg/m2 every 14 days). Results of a consecutive series treated by dose-intense PEFG regimen are herewith reported. MATERIAL AND METHODS Dose-intense PEFG was administered to chemotherapy-naive patients with stages III-IV PA, < 75 years, performance status (PS) > 50, till progressive disease or for a maximum of 6 months. RESULTS Between January 2004 and June 2005, 49 (31 or 63% metastatic) patients, median age 62 years, median PS 80, were treated with dose-intense PEFG. Partial response and stable disease was observed in 24 (49%) and 16 (33%) patients, respectively; 31 patients were progression-free at 6 months (PFS-6 = 63%). Median survival was 10.5 months and 1-year overall survival (OS) was 48% (95% confidence interval: 33-61%). Main grade 3-4 toxicity was: neutropenia in 26% of patients, stomatitis and fatigue in 8%, anaemia, diarrhoea, nausea/vomit in 6%, febrile neutropenia and thrombocytopaenia in 4%, hand-foot syndrome in 2%. CONCLUSION When compared with 84 patients treated by classical PEFG at the same institution, dose-intense PEFG was not inferior in terms of PFS-6 (63 versus 57%), 1-year OS (48 versus 42%) and response rate (49 versus 49%); it allowed to increase dose intensity for gemcitabine by 32%, for cisplatin and epirubicin by 36% (FU reduced by 3%), to significantly reduce grade 3-4 hematological toxicity (neutropenia: 26 versus 86%; P < 0.00001; thrombocytopaenia: 4 versus 58%; P < 0.00001) and to reduce by one-third the number of outpatient accesses. The new PEFG schedule appears more suitable for clinical use and should be preferred as a basis for further development of therapeutic strategies against pancreatic cancer.
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Affiliation(s)
- M Reni
- Department of Oncology, San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy.
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Mohammad RM, Banerjee S, Li Y, Aboukameel A, Kucuk O, Sarkar FH. Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts. Cancer 2006; 106:1260-8. [PMID: 16475211 DOI: 10.1002/cncr.21731] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The activation of nuclear factor kappaB (NF-kappaB) contributes to drug resistance in pancreatic carcinoma. The authors previously showed that the soy isoflavone genistein down-regulates the activation of NF-kappaB in many carcinoma cell lines in vitro. In the current study, they focused their investigation on testing whether the inactivation of NF-kappaB by genistein could enhance cisplatin-induced cell growth inhibition and apoptosis in BxPC-3 cells in vitro and antitumor activity of cisplatin in vivo. METHODS BxPC-3 cells were preexposed to 25 microM genistein for 24 hours and then exposed to cisplatin (0.5 microM) for an additional 72 hours. A cell growth inhibition assay, an apoptosis assay, and an NF-kappaB electrophoretic mobility shift assay were conducted. For the in vivo study, a xenograft model of BxPC-3 cells in severe combined immunodeficient mice was used. Genistein was given at a dose of 800 microg/kg orally for 5 days, cisplatin was given at a dose of 9 mg/kg as an intraperitoneal bolus, and another group of mice received both cisplatin and genistein (given on Day 1 concurrently followed by genistein for 4 days). RESULTS The combination of 25 microM genistein with 0.5 microM cisplatin resulted in significantly greater growth inhibition (P < 0.01) and more apoptosis in BxPC-3 cells compared with either agent alone. Preexposure of BxPC-3 cells to genistein abrogated cisplatin-induced activation of NF-kappaB, which appeared to be consistent with the authors' hypothesis. The authors also demonstrated for the first time that the in vivo effect of genistein enhanced the antitumor activity of cisplatin. The tumor weight for the control, genistein, cisplatin, and combined genistein and cisplatin mice was 940 mg, 762 mg, 261 mg, and 108 mg, respectively. Most important, for the first time, the authors observed that the DNA-binding activity of NF-kappaB was inactivated in genistein-treated animal tumors, whereas cisplatin significantly induced NF-kappaB DNA binding activity, and this was completely abrogated in genistein-pretreated tumors that were exposed to cisplatin, consistent with the in vitro data. CONCLUSIONS Overall, the current results were consistent with the authors' hypothesis and suggested that pretreatment of pancreatic carcinoma cells with genistein down-regulates NF-kappaB activity and contributes toward enhancing the apoptosis-inducing effect of cisplatin, leading to greater antitumor activity in vivo.
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Affiliation(s)
- Ramzi M Mohammad
- Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
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Charvát J, Linke Z, Horáèková M, Prausová J. Implantation of central venous ports with catheter insertion via the right internal jugular vein in oncology patients: single center experience. Support Care Cancer 2006; 14:1162-5. [PMID: 16596418 DOI: 10.1007/s00520-006-0073-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2006] [Accepted: 03/22/2006] [Indexed: 01/19/2023]
Abstract
AIM OF WORK Evaluation of suitability and safety of venous port implantation with catheter insertion via the right internal jugular vein in oncology patients. PATIENTS AND METHODS One hundred one totally implantable venous ports were placed in 100 patients with malignancies from January 1, 2003 until March 31, 2005. Catheter of venous port was preferably inserted via the right internal jugular vein. We recorded a number of successful implantations using this venous approach and the rate of complications during the procedure and follow-up. MAIN RESULTS Ninety-seven catheters (96%) of totally implantable venous ports were inserted via the right internal jugular vein in 96 patients, and only in four cases were we not able to access this vein. We had no complications related to catheter insertion via the right internal jugular vein. Follow-up was made in all 96 patients with a total access days of 41 in 151 days (mean: 407 days). Premature catheter removal was required in six (6.2%, 0.144 per 1,000 access days) due to complications: three catheter dislocations/malfunctions (3.1%, 0.072 per 1,000 access days), one port-related sepsis, one pocket port infection, and one decubitus over port (1%, 0.024 per 1,000 access days). Six venous ports were removed after completion of the treatment at the patient's request. CONCLUSION The placement of totally implantable venous ports with catheter insertion via the right internal jugular vein has a high success rate without any early complications. Follow-up also demonstrates a low incidence of late complications requiring port removal.
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Affiliation(s)
- J Charvát
- Medical Department of 2nd Faculty of Medicine of Charles University and the Motol Faculty Hospital, Prague, Czech Republic.
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Ikeda O, Kusunoki S, Kudoh K, Takamori H, Tsuji T, Kanemitsu K, Yamashita Y. Evaluation of the Efficacy of Combined Continuous Arterial Infusion and Systemic Chemotherapy for the Treatment of Advanced Pancreatic Carcinoma. Cardiovasc Intervent Radiol 2006; 29:362-70. [PMID: 16502181 DOI: 10.1007/s00270-004-7177-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
PURPOSE To evaluate the effects of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in patients with advanced pancreatic carcinoma. METHODS CTAI was performed in 17 patients with stage IV pancreatic cancer with (n = 11) or without (n = 6) liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The inferior pancreatic artery (IPA) was embolized to achieve delivery of the pancreatic blood supply through only the celiac artery. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. Treatment effects were evaluated based on the primary tumor size, liver metastasis, and survival time and factors such as tumor size, tumor location, and stage of pancreatic carcinoma; the embolized arteries were analyzed with respect to treatment effects and prognosis. RESULTS A catheter was fixed in the gastroduodenal artery and splenic artery in 10 and 7 patients, respectively. Complete peripancreatic arterial occlusion was successful in 10 patients. CT showed a decrease in tumor size in 6 of 17 (35%) patients and a decrease in liver metastases in 6 of 11 (55%) patients. The survival time ranged from 4 to 18 months (mean +/- SD, 8.8 +/- 1.5 months). Complete embolization of arteries surrounding the pancreas was achieved in 10 patients; they manifested superior treatment effects and prognoses (p < 0.05). CONCLUSION In patients with advanced pancreatic cancer, long-term CTAI with systemic chemotherapy appeared to be effective not only against the primary tumor but also against liver metastases. Patients with successfully occluded peripancreatic arteries tended to survive longer.
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Affiliation(s)
- O Ikeda
- Department of Diagnostic Radiology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Japan.
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Gockel I, Kneist W, Junginger T. Incurable Esophageal Cancer: Patterns of Tumor Spread and Therapeutic Consequences. World J Surg 2006; 30:183-90. [PMID: 16425075 DOI: 10.1007/s00268-005-7861-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND The aim of the study was to determine if the two histologic tumor types in esophageal cancer exhibit different behavior at advanced tumour stages and require a differentiated therapy. PATIENTS AND METHODS From November 1997 to December 2003, 268 patients presented with esophageal carcinoma. Esophagectomy was contraindicated in 88 (32.8%) patients (75 men, 13 women) with a median age of 64.7 (42-83) years. Fifty-six (63.6%) had squamous cell carcinoma; adenocarcinoma was identified in 31 (35.2%). RESULTS The causes of incurable disease were non-resectable distant metastases in 32 (36.4%) patients, local tumor spread in 25 (28.4%), and general operative risk in 19 (21.5%). Surgical intervention was contraindicated in 7 patients because of a combination of general inoperability and local tumor spread, or the presence of distant metastases at the time of diagnosis (4 patients declined to undergo surgery and in one patient esophageal resection and reconstruction was technically not possible). The incurability rate for squamous cell carcinoma was 44.6% because of the presence of local tumor spread, compared to a rate of 12.4% for adenocarcinoma. Adenocarcinomas with proven hematogenic metastases were characterized by a higher incurability rate (64.5% vs. 21.4%) (P=0.0014). The prevalence of technical causes of inoperability or of poor general condition was similar in both patient groups (P>0.05). The median 1-year survival rates estimated (Kaplan-Meier) were 36.5% for patients with squamous cell carcinoma and 23.7% for patients with adenocarcinoma (P=0.051). Therapeutic measures had a significant influence on the prognosis: patients without tumor-specific therapy survived 3.4 (0-24) months; those with radiochemotherapy 10.6 (0-25) months; those with radiotherapy 11.0 (0-65) months; and those with chemotherapy 16.5 [0-16.5] months (log-rank test: P=0.0229). In the multivariate analysis, the therapeutic measures (P=0.0126) and tumor localization (P=0.0474) proved significant for prognosis, but were not the cause of incurability (P=0.0948). CONCLUSIONS The histologic tumor type does not represent an independent prognostic factor in patients with incurable disease. Rather, the prognosis is dependent on the suitability of the induction of tumor-specific therapeutic measures. These are also recommended in patients with incurable disease after consideration of the extent of tumor spread, provided the performance of the selected measures is justified by the general condition of the patient and the expected prognosis.
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Affiliation(s)
- Ines Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University of Mainz, Langenbeckstr. 1, Mainz, D-55101, Germany.
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Feliu J, Sáenz JG, Jaráiz AR, Castañón C, Cruz M, Fonseca E, Lomas M, Castro J, Jara C, Casado E, León A, Barón MG. Fixed dose-rate infusion of gemcitabine in combination with cisplatin and UFT in advanced carcinoma of the pancreas. Cancer Chemother Pharmacol 2006; 58:419-26. [PMID: 16404636 DOI: 10.1007/s00280-005-0167-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2005] [Accepted: 11/14/2005] [Indexed: 10/25/2022]
Abstract
BACKGROUND Gemcitabine is currently considered the standard treatment for advanced pancreatic cancer (APC). Cisplatin and a fluoropyrimidine have some activity in the treatment of this cancer. The aim of this trial is to evaluate the efficacy and toxicity of a fixed dose-rate infusion of gemcitabine associated with cisplatin and UFT in patients with APC. PATIENTS AND METHODS Forty-six chemotherapy-naïve patients with APC that was either unresectable or metastatic were included in this phase II study. All of them had Karnofsky performance status > or =50 and unidimensionally measurable disease. Treatment consisted of gemcitabine 1,200 mg/m2 given as a 120-min infusion weekly for three consecutive weeks, cisplatin 50 mg/m2 on day 1 and oral UFT 400 mg/m2/day (in two to three daily doses) on days 1 to 21; cycles of treatment were given every 28 days. RESULTS A total of 208 cycles of chemotherapy were given with a median of 4 per patient. Fourteen patients (30%) achieved partial responses (95% CI 19-48%) and 17 (37%) had stable disease. The median time to progression was 5 months, and the median overall survival 9 months. Nineteen patients (49%; 95% CI 32-64%) had a clinical benefit response. Grade 3-4 WHO toxicities were as follows: neutropaenia in 26 patients (57%), with 5 cases of febrile neutropaenia (11%), thrombocytopaenia in 15 (33%), anaemia in six (13%), diarrhoea in 5 (11%), asthenia in 2 (4%) and mucositis in 1 (2%). Seven patients required hospitalisation for treatment-related complications. CONCLUSION A fixed dose-rate infusion of gemcitabine associated with cisplatin and UFT is active in patients with APC, though at the cost of considerable toxicity.
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Affiliation(s)
- J Feliu
- Servicio de Oncología Médica, Hospital La Paz, Paseo de la Castellana, 261, 28046, Madrid, Spain.
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Li Y, Ahmed F, Ali S, Philip PA, Kucuk O, Sarkar FH. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res 2005; 65:6934-42. [PMID: 16061678 DOI: 10.1158/0008-5472.can-04-4604] [Citation(s) in RCA: 281] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor kappaB (NF-kappaB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-kappaB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-kappaB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 micromol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 micromol/L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-kappaB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-kappaB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-kappaB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-kappaB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers.
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Affiliation(s)
- Yiwei Li
- Department of Pathology and Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
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Ducreux M, Mitry E, Ould-Kaci M, Boige V, Seitz JF, Bugat R, Breau JL, Bouché O, Etienne PL, Tigaud JM, Morvan F, Cvitkovic E, Rougier P. Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone in advanced pancreatic carcinoma patients. Ann Oncol 2004; 15:467-73. [PMID: 14998850 DOI: 10.1093/annonc/mdh098] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND A randomized phase II, open-label multicenter study evaluating oxaliplatin alone (OXA), infusional 5-fluorouracil alone (5-FU) and an oxaliplatin/infusional 5-FU combination (OXFU) in untreated, advanced pancreatic carcinoma (APC). PATIENTS AND METHODS Chemotherapy-naïve patients with advanced or metastatic, histologically/cytologically proven pancreatic carcinoma with measurable disease, received OXA [130 mg/m2, 2-h intravenous (i.v.) infusion] alone, OXA combined with 5-FU (1000 mg/m2/day, continuous i.v., days 1-4), or 5-FU alone, every 3 weeks. RESULTS Sixty-three patients (42 males/21 females) were treated: 17 patients/52 cycles OXA, 31 patients/ 175 cycles OXFU, 15 patients/41 cycles 5-FU, with a median of three, six and two cycles/patient, respectively. Patient characteristics were similar in all arms. Median age was 57 years (range 21-75), and 83% of patients had PS 0-1. Most patients (62%) had moderate to well-differentiated tumors, 90% had metastatic disease, 81% with liver metastases. All responses (three partial responses; WHO) occurred in the OXFU arm (10% response rate). Five of 32 patients evaluable for clinical benefit were responders (OXA, 14%; OXFU, 21%). Median time to progression and overall survival were higher in the combination arm (4.2 and 9.0 months, respectively) than either single-agent arm (OXA, 2.0 and 3.4 months; 5-FU, 1.5 and 2.4 months, respectively). Moderate hematotoxicity without morbidity was seen in all arms. Two OXFU patients had grade 3 oxaliplatin neurosensory toxicity. CONCLUSIONS With a 10% response rate, median overall survival of 9 months and an encouraging safety profile, the OXFU combination is effective, appears superior to infusional 5-FU and warrants further studies in APC patients.
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Affiliation(s)
- M Ducreux
- Institut Gustave Roussy, Villejuif, France
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23
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Li Y, Ellis KL, Ali S, El-Rayes BF, Nedeljkovic-Kurepa A, Kucuk O, Philip PA, Sarkar FH. Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line. Pancreas 2004; 28:e90-5. [PMID: 15097869 DOI: 10.1097/00006676-200405000-00020] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer chemotherapeutic strategies should be devised to provide higher tumor response and lower toxicity for combination chemotherapy. Genistein has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. The antitumor effects of genistein could be in part due to inactivation of NF-kappaB activity. In contrast, chemotherapeutic agents inadvertently induce NF-kappaB activity, which may lead to chemoresistance. In this study, we investigated whether the inactivation of NF-kappaB by genistein would enhance the efficacy of chemotherapeutic agents. BxPC-3 pancreatic cancer cells were pretreated with 30 micromol/L genistein for 24 hours and then exposed to lower concentrations of chemotherapeutic agents for an additional 24 hours. Cell growth inhibition assay, apoptosis assay, and NF-kappaB EMSA were performed. The combination of 30 micromol/L genistein with 1 nmol/L docetaxel or 100 nmol/L cisplatin elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced more apoptosis in BxPC-3 cells compared with single agents. Moreover, the NF-kappaB activity was significantly increased within 2 hours of docetaxel or cisplatin treatment, and the NF-kappaB-inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results clearly suggest that genistein pretreatment, which inactivates NF-kappaB activity, together with other cellular effects of genistein, may contribute to increased cell growth inhibition and apoptosis inducing effects of nontoxic doses of docetaxel and cisplatin, which could be a novel strategy for the treatment of pancreatic cancer.
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Affiliation(s)
- Yiwei Li
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
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Markham C, Stocken DD, Hassan AB. A phase II irinotecan-cisplatin combination in advanced pancreatic cancer. Br J Cancer 2003; 89:1860-4. [PMID: 14612893 PMCID: PMC2394443 DOI: 10.1038/sj.bjc.6601377] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2003] [Revised: 08/20/2003] [Accepted: 09/11/2003] [Indexed: 12/02/2022] Open
Abstract
We report a cisplatin and irinotecan combination in patients with biopsy-proven advanced pancreatic adenocarcinoma. Patients were selected from a specialist centre and required good performance status (KPS>70%), measurable disease on CT scan, and biochemical and haematological parameters within normal limits. Based on a two-stage phase II design, we aimed to treat 22 patients initially. The study was stopped because of the death of the 19th patient during the first treatment cycle, with neutropenic sepsis and multiorgan failure. A total of 89 treatments were administered to 17 patients. Serious grade 3/4 toxicities were haematological (neutropenia) 6%, diarrhoea 6%, nausea 7% and vomiting 6%. Using the clinical benefit response (CBR) criteria, no patients had an overall CBR. For responses confirmed by CT examination, there was one partial response (5%), three stable diseases lasting greater than 6 weeks (16%), with an overall 22% with disease control (PR+SD). The median progression-free and overall survival was 3.1 months (95% CI: 1.3-3.7) and 5.0 (95% CI: 3.9-10.1) months, respectively. Although this synergistic combination has improved the response rates and survival of other solid tumours, we recommend caution when using this combination in the palliation of advanced pancreatic cancer, because of unexpected toxicity.
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Affiliation(s)
- C Markham
- Liver Unit, University Hospital Birmingham NHS Trust (Queen Elizabeth), UK
| | - D D Stocken
- Cancer Research UK Clinical Trials Unit and Institute for Cancer Studies, University of Birmingham B15 2TT, UK
| | - A B Hassan
- Liver Unit, University Hospital Birmingham NHS Trust (Queen Elizabeth), UK
- Cancer Research UK Clinical Trials Unit and Institute for Cancer Studies, University of Birmingham B15 2TT, UK
- Bristol Haematology and Oncology Centre, Horfield Road, Bristol BS2 8ED, UK
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Yip D, Karapetis C, Strickland AH, Steer C, Holford C, Knight S, Harper P. A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies. Ann Oncol 2003; 14:864-6. [PMID: 12796023 DOI: 10.1093/annonc/mdg254] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Oral eniluracil/5-fluorouracil (5-FU) was shown in early clinical studies to have promising activity against gastrointestinal malignancies. Oxaliplatin in combination with 5-FU also has activity against these tumour types. The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in combination with oxaliplatin. PATIENTS AND METHODS Twenty-three patients with advanced gastrointestinal malignancies were recruited into this open-label study. Patients received a fixed dose of oxaliplatin (130 mg/m(2) on the first day of a 21-day cycle), and the dose intensity of oral eniluracil/5-FU was gradually increased by escalating the number of days of treatment per course. RESULTS The maximum tolerated dose intensity was eniluracil/5-FU 10.0/1.0 mg/m(2) twice daily for 16 days in combination with oxaliplatin 130 mg/m(2) on the first day of a 21-day cycle. Dose-limiting toxicities included vomiting and diarrhoea. The objective tumour response rate was 26% with a median duration of response of 15.3 weeks (95% confidence interval 8.5-22.1). Twenty-two patients (96%) experienced neurotoxicity (sensory neuropathy or cold-related dysaesthesia), although only two events were severe (grade 3). CONCLUSIONS The recommended dose for future study in patients with advanced gastrointestinal cancer is 10.0/1.0 mg/m(2) oral eniluracil/5-FU twice daily for 14 days in combination with oxaliplatin 130 mg/m(2) on the first day of each treatment cycle.
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Affiliation(s)
- D Yip
- Department of Medical Oncology, Guys Hospital, London, UK
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Mitsutsuji M, Suzuki Y, Iwanaga Y, Fujino Y, Tanioka Y, Kamigaki T, Ku Y, Kuroda Y. An experimental study on the pharmacokinetics of 5-fluorouracil regional chemotherapy for pancreatic cancer. Ann Surg Oncol 2003; 10:546-50. [PMID: 12794021 DOI: 10.1245/aso.2003.07.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Recently a few centers reported promising results of regional intra-arterial chemotherapy for pancreatic cancer. However, the detailed pharmacokinetics and the side effects of anticancer agents remain unclear. METHODS Catheters were introduced into the gastroduodenal artery and the splenic artery of dogs. In group I, arterial infusion of 5-fluorouracil (5-FU) was performed over 10 minutes. In group II, 5-FU was infused systemically. In group III, an intra-arterial infusion was repeated weekly three times. Blood samples and liver and pancreas tissue samples were obtained to determine 5-FU levels. In a subset of each group, the pancreas, duodenum, and liver were excised for histological analyses. RESULTS Immediately after the infusion of 5-FU, the portal level in group I was higher than that in group II. However, the mean systemic level in group I was lower than in group II. The mean tissue concentration in the pancreas in group I was significantly higher than that of group II. Histological examination revealed no microscopic alterations after treatment in all groups, including group III. CONCLUSIONS This fundamental study suggested that intra-arterial chemotherapy of 5-FU for pancreatic cancer allows higher regional drug delivery without adverse effects on normal regions of the pancreas, the duodenum, and the liver.
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Affiliation(s)
- Masaaki Mitsutsuji
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kobe University, Japan
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Evans TRJ, Pentheroudakis G, Paul J, McInnes A, Blackie R, Raby N, Morrison R, Fullarton GM, Soukop M, McDonald AC. A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophago-gastric adenocarcinoma. Ann Oncol 2002; 13:1469-78. [PMID: 12196374 DOI: 10.1093/annonc/mdf243] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The purpose of this study was to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose of capecitabine when used in combination with epirubicin and cisplatin (ECC) in patients with oesophageal or gastric adenocarcinoma. Response rate, progression-free survival (PFS) and overall survival were also determined, and the effect of previous oesophago-gastric surgery or concurrent oesophago-gastric cancer on the absorption and metabolism of capecitabine was evaluated. PATIENTS AND METHODS Patients with inoperable oesophago-gastric adenocarcinoma received up to six cycles of epirubicin (50 mg/m(2) i.v., 3-weekly), cisplatin (60 mg/m(2) i.v., 3-weekly) and capecitabine, the latter administered orally in an intermittent schedule (14 days treatment; 7-day rest period) at 3-weekly intervals. Patients were recruited into one of four escalating dose cohorts (500, 825, 1000 and 1250 mg/m(2) bd). Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level, with DLT assessed on the toxicity of the first cycle only. Blood sampling for pharmacokinetic analyses was performed over the first 10 h of day 1 of cycle 1. RESULTS Thirty-two patients, median age 63 years (range 32-76 years), ECOG performance status < or =2 with locally advanced (10) or metastatic (22) disease were recruited and were evaluable for toxicity. Two of five patients experienced DLT at 1250 mg/m(2) bd with grade II stomatitis (one patient) and grade III diarrhoea with febrile neutropenia (one patient). Cumulative toxicity for all cycles (n = 140) (worst grade per patient) includes grade IV oesophagitis (one patient), grade III diarrhoea (five), grade IV neutropenia with infection (seven), grade II stomatitis (four) and grade IV thrombocytopenia (one). Of 29 patients with evaluable disease, there was one complete response and six partial responses [24% response rate [95% confidence interval (CI) 10% to 44%]], a median PFS of 22 weeks (95% CI 17-27 weeks) and median overall survival of 34 weeks (95% CI 19-49 weeks). Capecitabine was rapidly absorbed after oral administration, with a t(max) of 1-2 h for capecitabine, DFCR (5'-deoxy-5-fluorocytidine) and DFUR (5'-deoxy-5-fluorouridine). The C(max) and AUC(0-)( infinity ) for capecitabine, DFCR and DFUR were similar to those observed in previous monotherapy studies of capecitabine taken after food. CONCLUSION A dose of 1000 mg/m(2) bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.
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Affiliation(s)
- T R J Evans
- CRC Dept of Medical Oncology, University of Glasgow, Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
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Yip D, Funaki B. Subcutaneous chest ports via the internal jugular vein. A retrospective study of 117 oncology patients. Acta Radiol 2002. [PMID: 12225477 DOI: 10.1034/j.1600-0455.2002.430405.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
PURPOSE To review image-guided chest port insertion using the right internal jugular vein as the access site of choice. MATERIAL AND METHODS One hundred and eighteen subcutaneous chest ports were placed via the internal jugular vein in 117 patients with malignancies using both fluoroscopic and US guidance in interventional radiology suites. RESULTS The technical success rate was 100% with no procedural complications. Follow-up was obtained in all patients with total access days of 40,450 days (mean, 342.8 days). Premature catheter removal was required in 8 patients (6.8%, 0.20 per 1,000 access days) due to non-treatable complications: 2 catheter occlusions/malfunctions (1.7%, 0.05 per 1,000 access days), 1 catheter-related skin erosion (0.85%, 0.024 per 1,000 access days), and 5 infections (4.2%, 0.15 per 1,000 access days). Two symptomatic right upper extremity venous thromboses also occurred (1.7%, 0.05 per 1,000 access days) that were treated successfully with anticoagulation. CONCLUSION Image-guided placement of internal jugular vein chest ports has a high success rate and low complication rate compared with reported series of unguided subclavian vein port insertion. The internal jugular vein should be used as the preferred venous access site compared to the subclavian vein.
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Affiliation(s)
- D Yip
- Department of Radiology, University of Chicago Hospitals, Chicago, IL 60637, USA
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Evans TRJ, Colston KW, Lofts FJ, Cunningham D, Anthoney DA, Gogas H, de Bono JS, Hamberg KJ, Skov T, Mansi JL. A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br J Cancer 2002; 86:680-5. [PMID: 11875725 PMCID: PMC2375305 DOI: 10.1038/sj.bjc.6600162] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2001] [Revised: 12/07/2001] [Accepted: 12/28/2001] [Indexed: 02/07/2023] Open
Abstract
Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states.
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Affiliation(s)
- T R J Evans
- CRC Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK.
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Karapetis CS, Yip D, Virik K, Strickland A, Ryder K, Cowling M, Harper PG. Epirubicin, cisplatin, and prolonged or brief infusional 5-fluorouracil in the treatment of carcinoma of unknown primary site. Med Oncol 2002; 18:23-32. [PMID: 11778966 DOI: 10.1385/mo:18:1:23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The cytotoxic regimen of epirubicin, cisplatin, and continuous infusional 5-fluorouracil (ECF) has demonstrated activity in a range of malignancies, including gastroesophageal, breast, and pancreatic cancers. Prolonged infusional central venous catheter (CVC) mediated therapy is not always feasible and modifications of the 5-fluorouracil (5FU) schedule have been reported. We reviewed our experience of both the standard and a modified ECF regimen in patients diagnosed with carcinoma of unknown primary site (CUPS). A retrospective analysis of all patients diagnosed with CUPS (31 adenocarcinoma and 5 poorly differentiated carcinoma) and treated with ECF between June 1994 and June 1998 was undertaken. Thirty-six patients, median age 56 (range: 24-74), were treated thrice-weekly with 50 mg/m2 epirubicin, 60 mg/m2 cisplatin, and 5-FU administered either by continuous infusion 200 mg/m2/d via a CVC (standard ECF) or as a 6-h infusion 600 mg/m2 through a peripheral venous catheter (modified ECF). Thirteen patients were treated with standard ECF and 23 received modified ECF. The median number of cycles administered was 4 (range: 1-10). Thirty-two patients had evaluable disease, seven (22%; 95% confidence interval: 8-36%) demonstrated a partial response, including three patients that received standard ECF and four treated with modified ECF. There were no complete responses. The median survival for all 36 patients was 9.0 mo. Median survival for patients treated with standard ECF was 11.7 mo as compared to 5.1 mo for the modified ECF schedule (p = 0.052). Liver involvement and elevation of serum CA19.9 were identified as possible adverse prognostic factors. Both regimens were well tolerated, with the only grade 3/4 toxicity recorded being leukopenia (four patients), nausea/vomiting (seven patients), and diarrhea (one patient). CVC complications in the standard ECF group were thrombosis (one patient) and infection (three patients). There were no treatment-related deaths. We conclude that ECF, whether modified or standard, has modest activity in the setting of CUPS. Patient survival is comparable to survival documented in previous reports of CUPS treatment. The apparent survival difference between the two ECF schedules may be the result of patient selection factors. The optimal treatment of CUPS remains unknown and can only be determined through randomized controlled trials.
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Affiliation(s)
- C S Karapetis
- Department of Medical Oncology, Guy's Hospital, London, United Kingdom
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31
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Pettersson F, Colston KW, Dalgleish AG. Retinoic acid enhances the cytotoxic effects of gemcitabine and cisplatin in pancreatic adenocarcinoma cells. Pancreas 2001; 23:273-9. [PMID: 11590323 DOI: 10.1097/00006676-200110000-00008] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
INTRODUCTION Retinoids, which are derivatives of vitamin A, are important factors involved in the control of biologic functions such as cell growth and differentiation, development, and carcinogenesis. We have shown previously that the naturally occurring retinoids all-trans-retinoic acid (ATRA) and 9-cisretinoic acid (9cRA) induce growth inhibition followed by apoptosis in pancreatic adenocarcinoma cells in vitro. AIM To evaluate the efficacy of retinoids in combination with the chemotherapeutic drugs gemcitabine and cisplatin. METHODOLOGY In vitro growth inhibition and induction of apoptosis by different combinations of retinoids and cytotoxic drugs were studied by using the T3M-4 and BxPc-3 cell lines. For in vivo studies, T3M-4 cells were injected subcutaneously in nude mice. RESULTS Pre-treatment of pancreatic adenocarcinoma cells with ATRA or 9cRA before the addition of the drugs resulted in significant reduction in cell number compared with treatment with the drugs alone. Pre-treatment with 9cRA followed by gemcitabine or cisplatin alone also resulted in a strong increase in the percentage of cells undergoing programmed cell death, or apoptosis. Furthermore, there was an indication that the combination of ATRA and gemcitabine caused increased apoptosis in vivo. CONCLUSION Our results clearly suggest the need for additional studies exploring the potential role of the combination of retinoids and gemcitabine in the management of pancreatic cancer.
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Affiliation(s)
- F Pettersson
- Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK
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32
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Reni M, Passoni P, Panucci MG, Nicoletti R, Galli L, Balzano G, Zerbi A, Di Carlo V, Villa E. Definitive Results of a Phase II Trial of Cisplatin, Epirubicin, Continuous-Infusion Fluorouracil, and Gemcitabine in Stage IV Pancreatic Adenocarcinoma. J Clin Oncol 2001; 19:2679-86. [PMID: 11352960 DOI: 10.1200/jco.2001.19.10.2679] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE: To evaluate the efficacy and toxicity of a cisplatin, epirubicin, gemcitabine, and fluorouracil (PEF-G) schedule on stage IV pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients ≤ 70 years, with no prior chemotherapy and with bidimensionally measurable stage IV pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or Karnofsky performance status between 50 and 70. Treatment consisted of 40 mg/m2 each of cisplatin and epirubicin day 1, gemcitabine 600 mg/m2 on days 1 and 8 every 4 weeks, and fluorouracil 200 mg/m2/d as a protracted venous infusion. RESULTS: Between April 1997 and April 1999, 49 patients from a single institution were eligible for the study. Altogether, 203 cycles (median, four cycles) of PEF-G were delivered. The objective response rate was 58% in 43 assessable patients and 51% in the intent-to-treat population. Fourteen patients had stable disease. Grade 3 or 4 World Health Organization neutropenia occurred in 51% of cycles, thrombocytopenia in 28%, anemia in 7%, stomatitis in 5%, and diarrhea, and nausea, and vomiting in 2%. The median duration of response was 8.5 months. The median time to tumor progression was 7.5 months. The median survival was 11 months in the assessable population and 10 months in the intent-to-treat population. Clinical benefit was achieved in 22 (78%) of 28 assessable patients. CONCLUSION: PEF-G is a well-tolerated and safe regimen; it obtained a very high rate of durable responses and deserves further evaluation in a phase III trial.
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Affiliation(s)
- M Reni
- Department of Radiochemotherapy, San Raffaele H. Scientific Institution, Milan, Italy.
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33
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Hoff PM. The tegafur-based dihydropyrimidine dehydrogenase inhibitory fluoropyrimidines, UFT/leucovorin (ORZEL) and S-1: a review of their clinical development and therapeutic potential. Invest New Drugs 2000; 18:331-42. [PMID: 11081569 DOI: 10.1023/a:1006445214741] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Protracted intravenous regimens of fluorouracil (5-FU) may be superior and better tolerated than intravenous bolus dosing. An effective oral regimen would allow a protracted course of 5-FU without the need for central venous lines and the associated increase in complications. Approximately 85% of 5-FU is degraded by dihydropyrimidine dehydrogenase (DPD); inhibition of this enzyme pathway can increase the amount of circulating 5-FU. Two oral fluoropyrimidines commonly referred to as DPD inhibitory fluoropyrimidines, or DIFs, UFT plus leucovorin (LV) and S-1 are reviewed herein. These agents represent an approach to more convenient, less toxic 5-FU therapy. In two multicenter, randomized, phase III trials in patients with advanced colorectal cancer, UFT/LV produced equivalent activity compared with intravenous 5-FU/LV but with significantly less major toxicity. The predominant side effect of UFT, diarrhea, is generally self-limited and easily managed. Myelosuppression and hand-foot syndrome were rarely noted in the schedules used in these trials. S-1 has demonstrated promising activity in phase II trials conducted in patients with gastric, colorectal, breast, and head and neck cancers. Ongoing trials are defining the roles of these agents in a variety of malignancies.
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Affiliation(s)
- P M Hoff
- Department of Gastrointestinal Oncology and Digestive Diseases, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA
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34
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Feliu J, López Alvarez MP, Jaraiz MA, Constenla M, Vicent JM, Belón J, López Gómez L, de Castro J, Dorta J, González Barón M. Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. The ONCOPAZ Cooperative Group. Cancer 2000; 89:1706-13. [PMID: 11042564 DOI: 10.1002/1097-0142(20001015)89:8<1706::aid-cncr9>3.0.co;2-i] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Use of chemotherapy for advanced pancreatic carcinoma (APC) pursues a palliative objective. Gemcitabine is active against this tumor and shows in vitro synergism with 5-fluorouracil. UFT is a combination of tegafur (a prodrug of 5-flouorouracil) and uracil that can be given orally. The administration of UFT for several weeks may simulate the effects of a continuous infusion of 5-fluorouracil. The objective of the current study was to assess the efficacy and toxicity of the combination gemcitabine-UFT-leucovorin in the treatment of APC. METHODS Forty-two patients with bidimensionally measurable APC were included. The study regimen consisted of gemcitabine 1000 mg/m(2) once weekly for 3 consecutive weeks, followed by a 1-week rest, intravenous 6S-steroisomer of leucovorin (6SLV) 250 mg/m(2) in 2 hours on Day 1, oral 6SLV 7.5 mg/12 hours on Days 2-14, and oral UFT 390 mg/m(2)/day (in 2 doses) on Days 1-14. Cycles were repeated every 4 weeks for a minimum of 3 per patient unless progressive disease was detected. RESULTS One hundred eighty-three courses were given, with a median of 4 per patient. World Health Organization Grade 3-4 toxicity was: diarrhea in 7 patients (17%), leucopenia in 2 (5%), nausea/vomiting in 2 (5%), and anemia in 1 (4%). Among 38 patients evaluable for response, 6 achieved a partial response (16%; 95% confidence interval (CI), 6-31. 4), 15 had stable disease (39%), and 17 had progression (45%). Improvement in performance status and symptoms (pain, analgesic consumption, and weight) was present in 11 (29%) and 17 (45%) patients, respectively. Eighteen patients (47%; 95% CI, 31.5-54.5) experienced a clinical benefit response. CONCLUSIONS The combination of gemcitabine-UFT-6SLV is convenient and moderately active and shows a low toxicity for the palliative treatment of patients with APC.
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Affiliation(s)
- J Feliu
- Services of Medical Oncology, La Paz, Madrid, Spain
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35
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Hu JC, Bradman K, Taylor M, Leslie M, Parker MC. Pancreaticoduodenectomy after downstaging of pancreatic carcinoma by chemotherapy. J R Soc Med 2000; 93:432-3. [PMID: 10983509 PMCID: PMC1298089 DOI: 10.1177/014107680009300813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- J C Hu
- Department of Clinical Oncology, Guy's Hospital, London, UK
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36
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Homma H, Doi T, Mezawa S, Takada K, Kukitsu T, Oku T, Akiyama T, Kusakabe T, Miyanishi K, Niitsu Y. A novel arterial infusion chemotherapy for the treatment of patients with advanced pancreatic carcinoma after vascular supply distribution via superselective embolization. Cancer 2000. [DOI: 10.1002/1097-0142(20000715)89:2<303::aid-cncr15>3.0.co;2-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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37
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Parnis FX, Olver IN, Kotasek D, Norman J, Taylor A, Russell J, Patterson K, Keefe D, Marafioti T. Phase II study of epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) for carcinoma of unknown primary site. Ann Oncol 2000; 11:883-4. [PMID: 10997819 DOI: 10.1023/a:1008311919633] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- F X Parnis
- Ashford Cancer Centre, South Australia, Australia
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38
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Pettersson F, Colston KW, Dalgleish AG. Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro. Br J Cancer 2000; 83:239-45. [PMID: 10901377 PMCID: PMC2363480 DOI: 10.1054/bjoc.2000.1281] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9-cis-retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth inhibitors. They were also more effective on their own than in combination with 9cRA. Growth arrest correlated with an increased proportion of cells in the G0/G1 phase. Apoptosis was induced in the three cell lines by 9cRA, whereas neither EB1089 nor CB1093 had this effect. Furthermore, addition of EB1089 or CB1093 together with 9cRA resulted in significantly reduced apoptosis. Our results show that retinoic acids as well as vitamin D analogues have inhibitory effects on pancreatic tumour cells but different and antagonistic mechanisms seem to be employed.
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Affiliation(s)
- F Pettersson
- Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK
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39
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Wiernik PH. Current status of and future prospects for the medical management of adenocarcinoma of the exocrine pancreas. J Clin Gastroenterol 2000; 30:357-63. [PMID: 10875462 DOI: 10.1097/00004836-200006000-00003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Adenocarcinoma of the exocrine pancreas is one of the most refractory neoplasms to medical treatment. Although of marginal value, 5-fluorouracil (5-FU) alone or in combination with other agents or modalities has been the standard surgical adjuvant approach to localized unresectable tumor as well as the standard treatment for disseminated pancreatic cancer. Recently, a new chemotherapeutic agent, gemcitabine, has been shown to be somewhat more effective than 5-FU against metastatic pancreatic cancer. Treatment with gemcitabine usually results in a greater likelihood of objective response and better symptom control than treatment with 5-FU or drug combinations that include 5-FU. However, treatment with gemcitabine does not improve overall survival of patients with disseminated neoplasm. Newer promising agents such as 9-nitrocamptothecin have recently entered clinical trials, and novel modalities (e.g., gene therapy) are nearing full-scale clinical trial. There are reasons to believe that these and other new initiatives may soon significantly improve the medical management of adenocarcinoma of the exocrine pancreas.
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Affiliation(s)
- P H Wiernik
- Comprehensive Cancer Center at Our Lady of Mercy Medical Center, New York Medical College, Bronx, New York 10466, USA.
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40
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O'Neill VJ, Jeffrey Evans TR, Preston J, Moss J, Kaye SB. A retrospective analysis of Hickman line-associated complications in patients with solid tumours undergoing infusional chemotherapy. Acta Oncol 2000; 38:1103-7. [PMID: 10665770 DOI: 10.1080/028418699432437] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
We present a retrospective analysis of Hickman line use and associated complications in patients with solid tumours undergoing treatment with infusional chemotherapy. One hundred and ten lines were inserted in 94 patients (55 females and 39 males, median age 51), of whom 107 were placed under radiological screening, the remainder by a surgical approach. Catheters were in situ for a total of 9670 days (median 101 days, range 1-278). Fifty-five complications occurred during the lifespan of 39 catheters (35.5%), giving an overall complication rate of 4.03/1000 catheter days. Early complications included pneumothorax (4%), arterial puncture (1%) and failure of placement (1%). Late complications included sepsis (superficial and systemic) (24.5%), venous thrombosis (9%), line displacement (10%) and catheter blockage (1%). Fifteen episodes of systemic sepsis occurred in 12 patients, giving an overall sepsis rate of 1.55/1000 catheter days, while complications requiring catheter removal occurred in 20 cases (18% of insertions, 2.07/1000 catheter days). We conclude that the use of Hickman catheters as a means of long-term venous access in infusional chemotherapy patients is generally safe, but is associated with significant morbidity.
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Affiliation(s)
- V J O'Neill
- CRC Department of Medical Oncology Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
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41
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Brunet R, Fonck M. [Contribution of gemcitabine in the treatment of advanced pancreatic cancer]. Rev Med Interne 1999; 20:816-20. [PMID: 10522306 DOI: 10.1016/s0248-8663(00)88691-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Pancreatic cancer is one of the most common tumor of the gastrointestinal tract. CURRENT KNOWLEDGE AND KEY POINTS Because this malignancy is usually diagnosed at an advanced stage, its prognosis is poor, and patients are generally considered incurable at diagnosis. The traditional palliative approach to management of this tumor is chemotherapy. The most widely used agent is 5-FU, alone or in combination. Benefits of the treatment are still poor: the overall survival time rarely exceeds 5 months, and no study has shown a response rate greater than 20%. FUTURE PROSPECTS AND PROJECTS Gemcitabine, a new antinucleoside agent, has led to promising results, as several phase II and III studies have demonstrated an increase in survival as compared with 5-FU, the overall 1-year survival rates being 18% and 2%, respectively (p < 0.002). Furthermore, even if only discrete results in terms of objective response rate have been achieved, gemcitabine decreases disease-related symptoms, thus benefiting to the patient's quality of life. The concept of clinical benefit therefore appears to be an important judgement criteria in the assessment of chemotherapy efficacy, and will certainly be extended to other malignant neoplasms.
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Affiliation(s)
- R Brunet
- Institut Bergonié, Bordeaux, France
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42
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Cascinu S, Frontini L, Comella G, Barni S, Labianca R, Battelli N, Casaretti R, Zonato S, Pirovano M, Catalano G, Cellerino R. Intensive weekly chemotherapy is not effective in advanced pancreatic cancer patients: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer 1999; 79:491-4. [PMID: 10027318 PMCID: PMC2362406 DOI: 10.1038/sj.bjc.6690076] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Twenty-two patients, with locally advanced unresectable and/or metastatic pancreatic carcinoma, received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 mg m(-2), supported by a daily administration of lenograstim at a dose of 5 microg kg(-1). Nineteen patients were men and three were women. Median age was 63 years (range 47-70). At study entry, pain was present in 15 out of 22 patients (68%) with a mean value of Scott-Huskisson scale of 27.6+/-23.8, whereas a weight loss >10% was present in 15 patients. After eight weekly treatments, three partial responses were achieved for a response rate of 13% (95% CI 0-26%), five patients had stable disease and 14 progressed on therapy. Pain was present in 9 out of 22 patients (40%) with a mean value of Scott-Huskisson scale of 12.3+/-18.4. Eight patients (36%) (three partial response and five stable disease) had a positive weight change. Toxicity was mild: WHO grade III or IV toxicity was recorded in terms of anaemia in 7 out of 188 cycles (3.7%), of neutropenia in 9 out of 188 cycles (4.7%) and of thrombocytopenia in 3 out of 188 cycles (1.5%). Median survival of all patients was 6 months. The outcome of this intensive chemotherapy regimen does not support its use in pancreatic cancer.
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Affiliation(s)
- S Cascinu
- Department of Medical Oncology, Ancona, Italy
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43
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Turci D, Cariello A, De Giorgi U, Marangolo M. La Chemioterapia Adiuvante Concomitante Del Carcinoma Pancreatico. TUMORI JOURNAL 1999. [DOI: 10.1177/030089169908501s10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Pancreatic cancer is a leading cause of cancer death. Despite improvement in diagnosis and treatment in the last 15 years, mortality rates essentially equal the incidence of the disease. Combination treatment with chemoradiation yields up to now better results than chemotherapy or radiotherapy given alone in consideration of substantial radio and chemoresistance of the cancer cells. This study will review the most important literature data about combination adjuvant treatment and preoperative (primary) chemoradiation in pancreatic cancer. Some other reports will be given on locoregional chemotherapy and finally a brief view on a possible perspective for promising future treatments coming from data of molecular pathology.Adjuvant chemoradiation after surgery has been shown to be superior to operation alone in potentially resectable pancreatic cancer in many studies, in terms both of local control and median overall survival. Unfortunately, a consistent percentage of patients cannot receive adjuvant treatment since late recovery after surgery or postoperative morbidity. Owing to this last reason, many authors prefer primary chemoradiation in potentially resectable pancreatic cancer; neoadjuvant treatment find out its background in other relevant biological and clinical evaluations.Some studies report encouraging results with primary chemoradiation using 5-fluorouracil. Other experiences with relatively new drugs, with potent radiosensiting effect, such as gemcitabine or taxol are going on; many of these are phase I studies. Clinical research in the field of preoperative treatment is up to now emerging in some importants Oncological Institutions. The principal actual aim seems to be that of forsee periods of treatment which will be brief and use the dose of chemotherapy that is active, giving acceptable toxicity.Ongoing trials will give, in the next years, the answer about the improvement of efficacy of treatments largely expected by all researchers.
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44
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Cascinu S, Graziano F, Catalano G. Chemotherapy for advanced pancreatic cancer: it may no longer be ignored. Ann Oncol 1999; 10:105-9. [PMID: 10076729 DOI: 10.1023/a:1008205515591] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Two case histories are reported here in which a chemotherapeutic approach improved the clinical conditions of patients with advanced pancreatic cancer. Until recently, chemotherapy was considered ineffective in pancreatic cancer, and most oncologists treated these patients with best-supportive-care only. Enthusiasm for systemic therapy of advanced pancreatic cancer is again growing, spurred by the advent of new drugs and new treatment endpoints such as life quality and symptom palliation. Gemcitabine, the most intensively-investigated new drug in pancreatic cancer, has shown an advantage in both survival and clinical benefit over that of 5-fluorouracil (5-FU). Other new drugs such as taxanes have shown interesting levels of activity, and are deserving of further evaluation. Although these results are far from conclusive and are only partially satisfactory, they represent a significant step forward in the treatment of advanced pancreatic cancer.
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Affiliation(s)
- S Cascinu
- Section of Experimental Oncology, Azienda Ospedaliera Ospedale S. Salvatore, Pesaro, Italy
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45
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Abstract
Pancreatic cancer is widely regarded by medical personnel and the lay public as one of the most dreaded of all diagnoses. Although in selected series of operable patients the chance of long term survival may reach 20%, most patients have unfavourable disease at the time of diagnosis, and for the entire group of newly diagnosed patients, 5-year survival is rare. This grim outlook results from a combination of factors, including an anatomical location which makes early detection by screening tests or by symptoms difficult, a high tendency for spread to regional lymphatics and the liver, a poor profile of sensitivity to chemotherapeutic agents and the poor medical condition of many patients at the time of diagnosis. These factors mean that it is particularly important that at the time of diagnosis these patients are carefully evaluated, and that they and their families are fully aware of the treatment options available to them and the associated potential risks and benefits. For localised cancers, surgical resection alone offers the potential for long term survival. The addition of postoperative radiation therapy (RT) predictably improves local control but has minimal impact on survival, which is primarily determined by the development of liver metastases. Randomised trial data support the use of combined fluorouracil (5-FU) chemotherapy and RT in patients who have undergone pancreatectomy and have negative margins, although the benefits are modest and the relevant randomised trials enrolled relatively small patient numbers. For patients with marginally resectable tumours, the feasibility has been demonstrated of using chemotherapy plus RT to reduce tumour size before resection, but it is unclear whether this approach will benefit a significant number of patients. Tumours which are unresectable because of local advancement (involvement of major vessels or regional nodes) can be treated with RT alone or in combination with chemotherapy, but survival past 2 years is uncommon. Patients with liver metastases have a poor prognosis. As part of a programme of supportive care, some of these patients may receive cytotoxic therapy, the goal of which is to relieve cancer-related symptoms such as pain from the primary tumour or metastatic sites, or weakness, nausea and anorexia which may be associated with liver metastases. Although the objective response rate of chemotherapy agents is low, in an individual patient they may produce an adequate response and acceptable toxicity so that the patient experiences overall improvement in symptoms. The mainstay of chemotherapy for pancreatic cancer, as with other gastrointestinal cancers, has been fluorouracil. However, recent clinical data have shown that gemcitabine produces similar results in terms of response rate and survival, with more acceptable toxicity, so that the quality of life was judged to be better than with fluorouracil. Pancreatic cancer provides a fertile ground for testing new, biologically based approaches to cancer therapy because of the limited success of currently available treatments.
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Affiliation(s)
- J R Sporn
- Division of Hematology-Oncology, University of Connecticut Health Center, Farmington 06030-1315, USA.
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46
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47
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Gogas H, Lofts FJ, Evans TR, Daryanani S, Mansi JL. Are serial measurements of CA19-9 useful in predicting response to chemotherapy in patients with inoperable adenocarcinoma of the pancreas? Br J Cancer 1998; 77:325-8. [PMID: 9461005 PMCID: PMC2151236 DOI: 10.1038/bjc.1998.50] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Thirty-nine patients with inoperable adenocarcinoma of the pancreas were studied (27 male, 12 female; median age 60 years, range 39-75 years). All patients received chemotherapy with continuous infusion 5-fluorouracil with intravenous bolus epirubicin followed by cisplatin, repeated every 21 days for a total of six cycles and were evaluable for response. Serum CA19-9 concentrations were obtained at baseline and before each cycle. A rise or fall in the tumour marker was defined as a greater than 15% increase or decrease in the marker on two consecutive occasions 3 weeks apart. A plateau in the tumour marker was defined as a less than 15% decrease or increase on two occasions. Changes in marker expression were compared with serial computerized tomography scanning before treatment and after the third and sixth cycle of chemotherapy. Thirty-five of 39 patients had an elevated CA19-9 (87.9%). Thirteen (36.2%) exhibited a decrease, seven (19.4%) a plateau and 16 (44.4%) patients had a progressive rise in serum CA19-9. The sensitivity of CA19-9 was 67% for predicting a partial response and 86% for progressive disease. The median survival for the 13 patients exhibiting a reduction was 333 days, for the seven patients exhibiting a plateau 253 days and for those who had a progressive rise 185 days. The difference in median survival between the group of patients with > 15% decrease and those with > 15% increase of CA19-9 was significant (P = 0.001). In the cohort of patients who exhibited a reduction in CA19-9, no tumour progression was seen, and the reduction occurred during the first three cycles of treatment. Thus, interval scanning may be avoided in this group of patients.
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Affiliation(s)
- H Gogas
- Department of Oncology, St George's Hospital, London, UK
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Lofts FJ, Evans TR, Mansi JL, Glees JP, Knight MJ. Bile duct stents: is there an increased rate of complications in patients receiving chemotherapy? Eur J Cancer 1997; 33:209-13. [PMID: 9135490 DOI: 10.1016/s0959-8049(96)00365-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The aim of this study was to determine whether palliative chemotherapy accelerates the rate of biliary stent occlusion, in patients with a malignant biliary obstruction. Such treatment can induce neutropenia and increase the risk of bacterial sepsis. Overgrowth of bacteria within the bile of patients receiving chemotherapy could accelerate the rate of stent occlusion. Retrospective analysis of treatment records for 80 consecutive patients with a diagnosis of adenocarcinoma arising from the pancreas, bile ducts or gall bladder was conducted. Two groups were identified, those with a biliary stent in situ (primary stent group: 47/80; 59%) at the time of referral and those without (no stent group: 33/80; 41%). The majority of patients went on to receive chemotherapy, 64% and 70% in the primary stent group and no stent group, respectively. The rate of febrile neutropenia was similar in the two groups (5% versus 7% of all chemotherapy cycles in the primary stent group and no stent group, respectively). The rate of stent occlusion was not significantly different between those exposed to chemotherapy (37%; 95% CI 20-54%) and those unexposed (39%; 95% CI 19-59%). Similarly, the mean duration of patency was not shortened by chemotherapy (105 days in the chemotherapy group versus 119 days in the non-chemotherapy group; P = 0.97, Mann-Whitney U-test). We conclude that there is no evidence of increased rate of bile duct-related complications in patients receiving chemotherapy. In particular, we find no indication for the use of prophylactic antibiotics.
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Affiliation(s)
- F J Lofts
- Department of Medical Oncology, St George's Hospital, London, U.K
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